We propose that the inability of the accessory HIV-1 Nef protein to inhibit T cell activation and apoptosis contributes to the high levels of immune activation and accelerates progression to AIDS. This hypothesis is based on our findings that - in strict contrast to HIV-1 Nefs - HIV-2 and most SIV Nefs down-regulate TCR/CD3 and inhibit T cell activation and apoptosis in HIV-1-infected primary cells. In contrast, other Nef functions such as up-regulation of the MHC-ll-associated invariant chain (li) are conserved among most or all primate lentiviruses. The specific aims of this proposal are to: SA1. Clarify the relevance of Nef-mediated up-modulation of li expression for AIDS pathogenesis. Stable surface expression of li prevents MHC-II peptide presentation and might impair helper T cell responses. We have generated SIVmac Nef variants allowing to clarify whether this Nef function affects helper T cell responses and the clinical course of infection in the SIV/macaque model. SA2. Elucidate how various HIV and SIV Nefs manipulate the function of T cells and APCs. Primary T cells and APCs will be transduced with proviral HIV-1 or SIV constructs co-expressing GFP and HIV or SIV nef alleles, exposed to different stimuli and subsequently evaluated for proliferation, viral spread, expression of activation markers and formation of the immunological synapse. We want to generate new information on how HIV and SIV Nefs manipulate the interaction between APCs and T cells. Another goal is to elucidate whether T cells form humans, macaques and Agms respond differently to activation. SA3. Understand the role of Nef-mediated down-modulation of TCR-CD3 in the pathogenesis of primate lentiviruses. We will generate SIVmac239 and SIVagm variants expressing nef alleles, which differ in their ability to down-modulate TCR-CD3 and evaluate their pathogenicity in the SIV/macaque and in African green monkeys, rrespectively. The results will clarify whether the inability of SIV to down-modulate TCR-CD3 will result in higher levels of T cell activation and accelerated CD4+ T cell depletion. Understanding the mechanisms underlying the low levels of immune activation and hence what enables naturally SIV-infected monkeys to prevent disease progression might lead to novel strategies allowing to delay or even prevent the development of AIDS in HIV-1-infected individuals. [unreadable] [unreadable] [unreadable]